Acute Neurological ICU Sedation Trial (ANIST)



Status:Completed
Conditions:Hospital
Therapuetic Areas:Other
Healthy:No
Age Range:18 - 80
Updated:10/14/2017
Start Date:April 2005
End Date:June 2008

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Dexmedetomidine (Precedex, Hospira) is a "super" selective alpha2-agonist - 8-10x more avid
binding to alpha2 receptors than clonidine - and may have particularly favorable
characteristics as a continuous i.v. infusion sedative for critically ill neuroscience
patients. Its combination of anxiolysis, analgesia, without undue lethargy may make it an
ideal agent where frequent neurological examinations are important (12). Unclear, however, is
whether Precedex is superior to current common i.v. sedation protocols, and if there are any
undue concerns of this agent on cerebral physiology and cortical stimulation.

Dexmedetomidine has shown promise in small case series to be an efficacious sedative agent in
the intensive care unit (ICU) setting, in both post-surgical and medical patients (10,18-21).
A recent publication reported on the efficacy in a small series of medical patients (n=12),
but as part of the exclusion criteria were any serious nervous system trauma or direct CNS
pathology (21).

A potential advantage of dexmedetomidine as a sedative agent compared to current popular
classes of drugs, particularly propofol, benzodiazepines, and narcotics, is the nominal
effect on reduction of level of arousal. Experience suggests that this agent may induce
effective degrees of sedation without concomitant loss of attentive behavior and cognition
following low levels of auditory or tactile stimulation. Thus, neurological assessment may be
preserved while achieving the goal of a non-agitated or anxious patient. Additionally, the
combination of both sedative/anxiolytic and analgesic action of dexmedetomidine may permit
single drug use for both sedation and pain control during the post-operative and medical ICU
period.

The cerebral effects of alpha2-agonists have been modestly studied in the clinical
environment, and only in normal volunteers (13). As expected, cerebral blood flow decreased
following initiation of the sedative, coincident with the expected diminishment of global
cerebral metabolism. No studies have evaluated dexmedetomidine in patients suffering from
neurological injury, the very population that may most benefit from the agent's sedative
characteristics. Thus, it is imperative that a safety & efficacy study be carried out in a
population of both medical and post-operative neuroscience patients. From an intraoperative
perspective, dexmedetomidine has been effectively used as a sedative for both awake and
sedation cases (1,2,4,16). Some evidence suggests prolonged cognitive deficits may persist
beyond the sedative action of the drug (4).

One concern in the neuroscience patient population is laboratory evidence that
alpha2-agonists may lower the seizure threshold (11). Such data has been shown for both
clonidine and dexmedetomidine.

Therefore, to provide a comprehensive evaluation leading to successful safety & efficacy data
for this sedative, it will be important to perform the following three studies. All three
studies will be done concurrently but enrollment between the three studies will be mutually
exclusive.

Study 1: Evaluation of Quality of Sedation: Does dexmedetomidine provide superior sedative
characteristics relative to current standard agents in patients with neurological
dysfunction? The metrics for such a study will include -

1. Pharmacodynamic ease of sedation: time to goal, required nursing interventions to goal;

2. Quality & consistency of sedation: ability to examine the patient, number of required
titration interventions;

3. Rapid weaning: time to off and no residual effect both hemodynamic & neurologic;

4. Systemic hemodynamic alterations requiring drug infusion adjustment or medical
intervention;

5. Side effect & toxicity of sedative infusion: neurological dysfunction - cognitive,
motor, sensory; electrolyte/hematological/metabolic disturbances, alteration of drug
levels.

Study 2: Alteration of Cerebral Physiology: Does Dexmedetomidine alter intracranial
physiology either in a favorable or unfavorable manner? The metrics for such a study will
include -

1. Measures of intracranial pressure (ICP), mean arterial pressure (MAP), cerebral
perfusion pressure (CPP);

2. Cognitive neurological state;

3. Cerebral saturation (venous) or direct cerebral oximetry (oxygen tissue level) in a
subset population with specific intracranial device.

Study 3: Alteration of Seizure Threshold Potential: Does Dexmedetomidine, using clinical
sedation infusion rates, reduce the seizure threshold or induce pre-ictal EEG changes in
normal and seizure-prone patients? The metrics for such a study will include -

1. Continuous scalp or epidural EEG monitoring in patients with seizure disorder;

2. Both hemispheres - normal and affected by seizures will be monitored to compare effects
of sedative agents on "normal" vs. epileptic foci.

Study 1: Inclusion Criteria:

Neuroscience patients in the NCCU who are:

1. 18-80 years of age;

2. Mechanically ventilated patients;

3. Requiring continuous sedation for a minimum of 9-11 hours (depending on whether or not
pt is post-operative), yet frequent neurological examinations or Patients with a NICSS
score > 0

4. Patient or family able to provide consent.

5. Considered to have guarded yet stable neurological state. Not fluctuating intracranial
pressure (ICP), cerebral perfusion pressure (CPP), or ongoing known cerebral ischemia
if ICP monitoring in place.

Study 1: Exclusion Criteria:

1. Pregnancy.

2. ICP> 30 mm Hg despite therapy if ICP monitored.

3. CPP <70 mm Hg if monitored.

4. Occurrence of: new cerebral stroke, hemorrhage, or change in edema by CT, increase in
ICP if monitored.

5. Neuromuscular paralysis.

6. Non-functional cognitive exam - not following commands.

7. Renal insufficiency: Serum Creatinine >2.0 mg/dl or estimated Cr Clearance <40.0
ml/min.

8. Hepatic disease: AST, ALT > 300, or INR > 1.7 not on anticoagulants.

9. Severe COPD with baseline arterial pCO2>50.

10. Suspected alcohol or substance withdrawal.

11. Hypotension - requiring pressor therapy to maintain baseline adequate CPP or mean
arterial pressure.

12. Cardiac arrhythmia - sinus bradycardia (HR <60), atrial fibrillation (>6 PVC's/min)

13. Bradycardia- heart rate less than 60 beats per minute.

14. Patient does not require mechanical ventilation.

Study 2: Inclusion Criteria:

Critically ill neuroscience patients who are:

1. 18-80 years of age;

2. Mechanically ventilated;

3. Require Intracranial Pressure (ICP) monitoring by either subarachnoid bolt (SA bolt),
or by an Intra-Ventricular Catheter (IVC).

4. Amenable for placement of intra-cerebral oxygen sensor or jugular bulb catheter.

5. Have GCS score > 5 that requires sedation.

6. Requiring continuous sedation for minimum of 9-11 hours (depending on whether or not
pt is post-operative) , yet frequent neurological examinations every 1-2 hours or
Patients with a NICSS score > 0

7. Patient or family able to provide consent.

Study 2: Exclusion Criteria:

1. Pregnancy;

2. ICP> 30 mm Hg despite therapy;

3. CPP <70 mm Hg;

4. Occurrence of: new cerebral stroke, hemorrhage, or change in edema by CT, increase in
ICP if monitored.

5. Continuous neuromuscular paralysis

6. Renal insufficiency: Serum Creatinine >2.0 mg/dl or estimated Cr <40.0 Clearance
ml/min.

7. Hepatic disease: AST, ALT > 300, or INR > 1.7 not on anticoagulants.

8. Severe COPD with baseline arterial pCO2>50.

9. Suspected alcohol or substance withdrawal.

Study 3: Inclusion Criteria:

Critically ill neuroscience patients who are:

1. 18-80 years of age;

2. Requiring continuous sedation for minimum of 9-11 hrs (depending on whether or not pt
is post-operative), yet frequent neurological examinations or Patients with a NICSS
score >0

3. Patient or family able to provide consent.

4. Mechanically ventilated patients;

5. Considered to have guarded yet stable neurological state. Not fluctuating ICP, CPP, or
ongoing known cerebral ischemia.

6. Presence of intra-operatively placed GRID electrode array or patients requiring
continuous EEG monitoring.

Study 3: Exclusion Criteria:

1. Pregnancy

2. Occurrence of: new cerebral stroke, hemorrhage, or change in edema by CT, increase in
ICP if monitored.

3. Continuous neuromuscular paralysis

4. Renal insufficiency: Serum Creatinine >2.0 or Cr Clearance <40.0

5. Hepatic insufficiency: AST, ALT> 300, or PT time > 1.7 not on anticoagulants.

6. Severe COPD with baseline arterial pCO2>50.

7. Suspected alcohol or substance withdrawal.
We found this trial at
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3400 N Charles St
Baltimore, Maryland 21205
410-516-8000
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